Intracerebral hemorrhage (ICH), bleeding into brain parenchyma from an arterial source, is the deadliest form of stroke and, in contrast to ischemic stroke, lacks any well-proved effective therapy. Although the majority of cases of ICH are spontaneous, ICH is also the most feared complication of warfarin, a medication indicated for long-term use in millions of Americans with atrial fibrillation. When associated with warfarin, ICH is even more devastating, with fatality over 50%. This research program aims to identify the genetic predictors of outcome from ICH and from ICH specifically related to warfarin. It will investigate apolipoprotein E genotype (APOE) and the factor XIII Val34Leu polymorphism. The objectives of this proposal are to determine 1) whether APOE predicts large hematoma volume in acute ICK, acute hematoma enlargement, and poor clinical outcome from acute ICH, and 2) whether factor XIII Val34Leu predicts hemorrhage recurrence in survivors of ICH, and is an independent protective factor for outcome from ICH related to warfarin. These objectives will be completed in a carefully characterized cohort of consecutive cases of spontaneous ICH. Because of the rapid growth in the understanding of both the human genome and the molecular basis of coagulation and vessel pathology, this cohort is likely to form the foundation of a powerful, open-ended search for genetic determinants of ICH and serve as a crucial tool for future studies. During the award period, in addition to serving as principal investigator for the proposed studies, Dr. Rosand will complete formal didactic training in research ethics, epidemiology, and biostatistics with a focus on the statistics applied to genetic studies of complex diseases. His mentor will be Dr. Steven M. Greenberg. Drs. James F. Gusella and Walter J. Koroshetz will serve as co-mentors. Upon conclusion of the award, Dr. Rosand, who has completed clinical fellowship training in stroke and critical care neurology, will have acquired the requisite skills to function as an independent investigator with specific expertise in genetic epidemiology. He will be trained to conduct fundamental studies in clinical and molecular epidemiology of acute cerebrovascular disease as well as pivotal clinical trials of novel therapeutic interventions for ICH.